The liver X receptors LXR alpha and LXR beta are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. Seminal studies with genetic and chemical tools were instrumental in the elucidation of cholesterol metabolism, gluconeogenesis, inflammation, and lipogenesis as signaling pathways that are controlled by the LXRs. First generation non-steroidal LXR agonists show beneficial effects in multiple animals models of human disease yet have not progressed in the clinic due to deleterious side effects in the liver. Numerous reports have appeared in the the recent literature that disclose new LXR signaling pathways and the identification of novel LXR chemotypes that may show improved therapeutic indices. This review will provide a brief historical perspective but will primarily focus on recent advances in LXR biology and chemistry.